Biocorrodible magnesium alloy implant

ABSTRACT

One embodiment of the invention relates to an implant comprising a base body made of a biocorrodible magnesium alloy. The magnesium alloy contains a plurality of statistically distributed particles, comprising one or more of the elements Y, Zr, Mn, Sc, Fe, Ni, Co, W, Pt and noble earths with the atomic numbers 57 to 71, or the particles comprise alloys or compounds containing one or more of the elements mentioned. The mean distance of the particles from each other is smaller than the hundredfold mean particle diameter.

TECHNICAL FIELD

The invention relates to an implant comprising a base body made of abiocorrodible magnesium alloy.

BACKGROUND

Implants are being employed in a wide variety of forms in modern medicaltechnology. They are used, for example, to support vessels, holloworgans and vein systems (endovascular implants, such as stents), forfastening and the temporary fixation of tissue implants and tissuetransplantations, but also for orthopedic purposes, such as nails,plates or screws. A particularly frequently used form of an implant isthe stent.

The implantation of stents has become established as one of the mosteffective therapeutic measures for the treatment of vascular diseases.Stents have the purpose of performing a stabilizing function in holloworgans of a patient. For this purpose, stents featuring conventionaldesigns have a filigree supporting structure comprising metal braces,which is initially present in compressed form for introduction into thebody and is expanded at the site of the application. One of the mainapplication areas of such stents is to permanently or temporarily dilateand hold open vascular constrictions, particularly constrictions(stenoses) of the coronary blood vessels. In addition, aneurysm stentsare also known, which are used primarily to seal the aneurysm. Thesupport function is additionally provided.

Stents comprise a peripheral wall with sufficient load-bearing capacityto hold the constricted vessel open to the desired extent and a tubularbase body through which the blood continues to flow without impairment.The peripheral wall is generally formed by a lattice-like supportingstructure, which allows the stent to be introduced in a compressedstate, in which it has a small outside diameter, all the way to thestenosis of the particular vessel to be treated and to be expandedthere, for example by way of a balloon catheter, so that the vessel hasthe desired, enlarged inside diameter. As an alternative, shape memorymaterials such as nitinol have the ability to self-expand when arestoring force is eliminated that keeps the implant at a smalldiameter. The restoring force is generally applied to the material by aprotective tube.

The implant, notably the stent, has a base body made of an implantmaterial. An implant material is a non-living material, which is usedfor applications in medicine and interacts with biological systems. Abasic prerequisite for the use of a material as implant material, whichis in contact with the body environment when used as intended, is thebody friendliness thereof (biocompatibility). Biocompatibility shall beunderstood as the ability of a material to evoke an appropriate tissueresponse in a specific application. This includes an adaptation of thechemical, physical, biological, and morphological surface properties ofan implant to the recipient's tissue with the aim of a clinicallydesired interaction. The biocompatibility of the implant material isalso dependent on the temporal course of the response of the biosystemin which it is implanted. For example, irritations and inflammationsoccur in a relatively short time, which can lead to tissue changes.Depending on the properties of the implant material, biological systemsthus react in different ways. According to the response of thebiosystem, the implant materials can be divided into bioactive, bioinertand degradable or resorbable materials.

Implant materials comprise polymers, metallic materials, and ceramicmaterials (as coatings, for example). Biocompatible metals and metalalloys for permanent implants comprise, for example, stainless steels(such as 316L), cobalt-based alloys (such as CoCrMo cast alloys, CoCrMoforge alloys, CoCrWNi forge alloys and CoCrNiMo forge alloys), technicalpure titanium and titanium alloys (such as cp titanium, TiAl6V4 orTiAl6Nb7) and gold alloys. In the field of biocorrodible stents, the useof magnesium or technical pure iron as well as biocorrodible base alloysof the elements magnesium, iron, zinc, molybdenum, and tungsten areproposed. The present invention relates to biocorrodible magnesium basealloys.

The use of biocorrodible magnesium alloys for temporary implants havingfiligree structures is made difficult in particular in that thedegradation of the implant progresses very quickly in vivo. So as toreduce the corrosion rate, this being the degradation speed, differentapproaches are being discussed. For one, it is attempted to slow thedegradation on the part of the implant material by developingappropriate alloys. In addition, coatings are to bring about a temporaryinhibition of the degradation. While the existing approaches arepromising, none of them has so far been implemented in a commerciallyavailable product. Regardless of the efforts made so far, there israther a continuing need for solutions that make it possible to at leasttemporarily reduce the in vivo corrosion of magnesium alloys.

SUMMARY

One or more of the disadvantages of the prior art mentioned above aresolved, or at least mitigated, by the implant according to theinvention. The implant according to the invention comprises a base bodymade of a biocorrodible magnesium alloy. The magnesium alloy contains aplurality of statistically distributed particles, comprising one or moreof the elements Y, Zr, Mn, Sc, Fe, Ni, Co, W, Pt and noble earths withthe atomic numbers 57 to 71, or alloys, or compounds containing one ormore of these elements. The mean distance of the particles from eachother is smaller than the hundredfold mean particle diameter.

In the development of magnesium materials so far, the corrosionresistance has always been improved by increasing the purity of themagnesium material. Iron, nickel, chromium, and cobalt are considered tobe critical elements in this context. Particles comprising intermetalliccompounds, particles of a different chemical nature (oxides, hydrides)or segregations (Al12Mg17) in magnesium materials result inmicrogalvanic corrosion due to the different electrochemical potential.This results in local corrosive processes, which massively acceleratethe corrosion rate of the material. For this reason, previously attemptshave been made to minimize the concentration of the particles to theextent possible.

The solution according to the invention, however, takes exactly theopposite approach. In magnesium materials, in general, the corrosionthat is observed attacks the material locally very inhomogeneously. Inthe process, cathodic processes occur, which are accompanied by therelease of hydroxide ions and the development of hydrogen, morespecifically at defined centers, namely the above-mentioned particles.The anodic dissolution process of the magnesium material takes place inthe surroundings of the cathodic center. The process can be divided intothe following partial reactions:

Anodic: Mg ->Mg²⁺+2e⁻

Cathodic: 2 H₂O+2e⁻ ->2 OH⁻+H₂

The anodic press is highly dependent on the pH value. For example, theMg corrosion is massively accelerated at pH<5, while it is massivelydecelerated at pH>10 and basically completely disrupted. Given thisbehavior, the release of hydroxide ions on the cathodic center leads tothe protection of the direct surroundings.

The invention is based on the realization that the corrosion of implantsmade of biocorrodible magnesium alloys can be delayed by adding aplurality of homogenously distributed particles to the material volume,a near-surface region, or the surface. The particles act as cathodiccenters within the above-mentioned meaning, which is to say, thehydrogen overvoltage is sufficiently low and the reaction can take placeat a high rate. The particles comprise one or more of the elements Y,Zr, Mn, Sc, Fe, Ni, Co, W, Pt and nobles earths with the atomic numbers57 to 71, or alloys, or compounds containing one or more of theseelements. In the present invention, the term ‘alloy’ shall covermetallic compositions of the elements, and also compositions in whichcovalent bonds exist between the elements. The alloys preferably containmagnesium. Compounds comprise in particular hydrides and carbides of theabove-mentioned elements.

Preferably, the particles consist of one or more of the elements Y, Zr,Mn, Sc, Fe, Ni, Co, W, Pt and nobles earths with the atomic numbers 57to 71, or alloys, or compounds consisting of one or more of theseelements.

Biocorrodible as defined by the invention denotes alloys in thephysiological environment of which degradation or remodeling takesplace, so that the part of the implant made of the material is no longerpresent in its entirety, or at least predominantly.

A magnesium alloy in the present case shall be understood as a metalstructure, the main constituent of which is magnesium. The mainconstituent is the alloying constituent having the highest weightproportion in the alloy. The proportion of the main constituent ispreferably more than 50% by weight, particularly more than 70% byweight. The alloy is to be selected in the composition thereof such thatit is biocorrodible. A possible test medium for testing the corrosionbehavior of a potential alloy is synthetic plasma, as that which isrequired according to EN ISO 10993-15:2000 for biocorrosion analyses(composition NaCl 6.8 g/l, CaCl₂ 0.2 g/l, KCl 0.4 g/l, MgSO₄ 0.1 g/l,NaHCO₃ 2.2 g/l, Na₂HPO₄ 0.126 g/l, NaH₂PO₄ 0.026 g/l). For this purpose,a sample of the alloy to be analyzed is stored in a closed samplecontainer with a defined quantity of the test medium at 37° C. and pH7.38. The samples are removed at intervals—which are adapted to theanticipated corrosion behavior—ranging from a few hours to severalmonths and analyzed for traces of corrosion in the known manner. Thesynthetic plasma according to EN ISO 10993-15:2000 corresponds to ablood-like medium and thus is a possible medium to reproducibly simulatea physiological environment as defined by the invention.

The term corrosion refers in the present example to the reaction of ametallic material with the environment thereof, wherein a measurablechange of the material is caused, which—when using the material in acomponent—results in an impairment of the function of the component. Thecorrosion process can be quantified by the provision of a corrosionrate. Swift degradation is associated with a high corrosion rate, andvice versa. Relative to the degradation of the entire base body, animplant that is modified as defined by the invention will result in adecrease of the corrosion rate.

The particles preferably have a mean diameter of 1 nanometer to 10micrometers, particularly preferred 500 nanometers to 3 micrometers, andmore particularly 1 to 2 micrometers.

In the surroundings of the cathodic center, protected regions develop asa result of the release of hydroxide ions. The majority of the protectedregion around an individual cathodic center depends on the size andcomposition of the particles and the surrounding matrix of the magnesiummaterial. The size of the protected area per particle should be at least1 square micrometer, preferably up to 100 square micrometers, with up to10000 square micrometers being particularly preferred.

Within the material, the area of the protected regions has a sizedistribution that is determined by the distribution of the particles.The protective effect on the total surface of the magnesium material isdependent on the number and size distribution of the protected regions.The number of particles on the surface of the base body is preferably1*10̂2 to 1*10̂6 particles per mm², or the number of particles in thevolume of the base body is 1*10̂3 to 1*10̂9 particles per mm³. A ratio ofthe mean particle diameter to the mean distance of the particles fromeach other preferably ranges between 1:2 and 1:100, and moreparticularly between 1:2 and 1:10.

The corrosion rate is quantitatively influenced by the cathodic centersas follow:

-   -   a) The protected total area A_protect is obtained by assuming        non-overlapping protected regions from the sum over the        distribution of the areas A_cathodic_center protected by the        individual cathodic centers:

$A_{protect} = {\sum\limits_{i = {1\mspace{11mu} \ldots \mspace{14mu} N}}A_{i}^{{cathodic}\mspace{14mu} {center}}}$

-   -   b) The corrosion rate R_corr is directly proportional to the        corrosion of the accessible sample area A_corr, wherein A_total        denotes the total area of the material:

$R_{corr} \propto A_{corr} \propto {A_{total} - A_{protect}} \propto {A_{total}( {1 - \frac{A_{protect}}{A_{total}}} )}$

As a result, assuming the same abrasion depth, the corrosion ratedecreases as the percentage of area of the protected region decreases.The percentages of area mentioned can be determined experimentally.

A particularly high protective effect is achieved precisely when asufficiently large number of cathodic centers is uniformly distributedin the material, and the overlap between the protected regions is assmall as possible. The optimal mean distance d_mean between cathodiccenters without overlap can be estimated from a statistical analysis ofthe distribution:

$d_{mean} = {2 \cdot \sqrt{\frac{A_{protect}}{N \cdot \pi}}}$

The protective effect can be increased both by a large number of smallprotected regions and by a small number of large protected regions. Themean distance of the particles preferably ranges between 200 nm and 100μm. The mean distance is in particular smaller than 20 μm.

The protected area per cathodic center is dependent on the chemicalnature of the cathodic center and the material matrix.

The claimed modification of the material can be applied not only to theentire material volume, but optionally can also be limited to thesurface or the near-surface region of an implant. In this way, it ispossible to deliberately introduce cathodic centers into the surface ofa workpiece by means of rolling. This creates an initial corrosionbarrier, and the degradation rate increases over time. The particles arepreferably incorporated in the surface or the near-surface region of thebase body. A relatively low corrosion rate then occurs at the beginningof the onsetting corrosive processes, said rate increasing over thecourse of time. This behavior is referred to as temporarily reducing thecorrosion rate. In the case of coronary stents, the mechanical integrityof the structure should be maintained for a period of three to sixmonths after implantation.

Implants as defined by the invention are devices introduced into thebody by a surgical procedure and comprise fastening elements for bones,such as screws, plates or nails, surgical suture material, intestinalclamps, vessel clips, prostheses in the area of hard and soft tissues,and anchoring elements for electrodes, particularly for pacemakers ordefibrillators. The implant is made entirely or partially of thebiocorrodible material. If only a part of the implant is made of thebiocorrodible material, this part is to be modified accordingly. Theimplant is preferably a stent.

A further concept of the invention is to provide two methods forproducing an implant comprising a main body made of a biocorrodiblemagnesium alloy, wherein the magnesium alloy contains a plurality ofstatistically distributed particles having the above-mentionedcomposition, and the mean distance of the particles from each other issmaller than the hundredfold mean particle diameter, and the particlesare incorporated in the surface or in a near-surface region of the basebody.

According to a first variant, the method comprises the following steps:

-   -   (i) providing a blank made of the biocorrodible magnesium alloy;    -   (ii) applying a non-aqueous suspension of particles having the        above-mentioned composition to the blank; and    -   (iii) rolling the particles into the surface or into the        near-surface region of the blank.

Accordingly, an oily suspension containing the particles to incorporatedis applied to the blank, from which the base body is to be shaped, andincorporated by rolling. This suspension can be used as a lubricant bothduring cold rolling and during hot rolling. By optimizing the volumeflow of the suspension, temperature, contact pressure and speed, theincorporation of the particles in the surface of the rolled magnesiummaterial can be optimized. The variant is suited in particular formagnesium alloys based on WE43.

According to a second variant, the method comprises the following steps:

-   -   (i) providing a blank made of the biocorrodible magnesium alloy;    -   (ii) applying particles having the above-mentioned composition        to the blank; and    -   (iii) melting the magnesium alloy onto the near-surface region        of the blank.

According to this variant, the particles to be incorporated are applieddirectly onto the blank, which later forms the base body. After that,the magnesium alloy is locally melted on the surface, for example bylaser treatment. After cooling, the particles are then embedded in thenear-surface region of the blank.

According to the two methods for producing an implant, the particlespreferably consist of preferably, the particles consist of one or moreof the elements Y, Zr, Mn, Sc, Fe, Ni, Co, W, Pt and nobles earths withthe atomic numbers 57 to 71, or alloys, or compounds consisting of oneor more of these elements.

DETAILED DESCRIPTION

The invention will be explained in more detail hereinafter based onembodiments.

Embodiment 1

An iron particle-containing (chemicals for the production are availablefrom Sigma-Aldrich, particle diameter smaller than 100 nm) suspension isapplied, for example by spraying or immersion, onto a plate-shaped blankmade of the magnesium alloy AZ31 so as to generate a film having astatistically homogeneous distribution of iron particles.

This suspension can be used as a lubricant both during cold rolling andduring hot rolling. The particles are incorporated in the surface of theblank by the rolling process. The particles not only increase thecorrosion protection, but also the wear resistance by increasing thehardness. The blank is subsequently processed into the base body of theimplant.

Embodiment 2

Tungsten particles (available from Sigma-Aldrich; particle diameterapproximately 150 nm) are applied in the form of a powder onto aplate-shaped blank made of the magnesium alloy AZ31 and homogeneouslydistributed by shaking When using complicated three-dimensionalstructures, it is also advantageous to use an adhesion-promoting polymerto coat the surface before the laser alloying process. By varying thepolymer to tungsten particle ratio, it is possible to directly adjustthe mean distance between tungsten particles.

The tungsten particles are incorporated into the magnesium alloy bylaser alloying. To this end, the workpiece is locally melted using ahigh-performance laser diode under argon inert gas. The laser output isbetween 1.2 and 1.6 kW, and the feed rate of the laser is 0.5 to 1.0m/min. The use of the argon prevents an oxidation of the magnesiummaterial and of the tungsten during processing.

Using the laser alloying technology, it is possible in particular tolocally protect a workpiece made of a magnesium alloy. In connectionwith stents, for example, sequential fragment of the implant can beachieved by locally influencing the degradation rate, for example byproviding the surfaces of the segment rings of a stent structure, butnot the longitudinal connecting struts of the segment rings, withcathodic centers according to the invention, whereby the struts degrademore quickly than the segment rings. Because the connecting strutsdissolve more quickly, high longitudinal flexibility is achievedquickly, wherein the load-bearing capacity of the segment rings is stillmaintained.

The particles provide not only corrosion protection, but also increasethe wear resistance against abrasion by increasing the hardness. Inaddition, by suitably selecting the particles and the compositionthereof, polymeric substances can be effectively bonded to the surface.These polymeric substances can have a corrosion-inhibiting effect on theone hand, and on the other hand, they may contain one or morepharmacological active ingredients, or exhibit a pharmacological effectthemselves.

The additional coating with a polymer can be technically implemented,for example, as follows. PLLA L214S (Boehringer Ingelheim) is dissolvedin a concentration of 1.6% (w/v) in chloroform and rapamycin is added asthe active substance. The active ingredient content preferably rangesbetween 15% and 20%, in relation to the solid matter content. Theimplant made of the modified magnesium alloy is immersed for 1 secondinto the solution using an underwater robot, pulled out, and aircontaining nitrogen is blown on so as to evaporate the solvent. Thisprocess is repeated until a sufficient layer thickness of approximately5 μm has been reached.

The embodiments also apply analogously to other biocorrodible magnesiumalloys and particle compositions.

It will be apparent to those skilled in the art that numerousmodifications and variations of the described examples and embodimentsare possible in light of the above teaching. The disclosed examples andembodiments are presented for purposes of illustration only. Otheralternate embodiments may include some or all of the features disclosedherein. Therefore, it is the intent to cover all such modifications andalternate embodiments as may come within the true scope of thisinvention.

1. An implant having a base body comprising a biocorrodible magnesiumalloy, wherein the magnesium alloy contains a plurality of statisticallydistributed particles, wherein the mean distance of the particles fromeach other is smaller than the hundredfold mean particle diameter, andthe particles comprise one or more of the elements Y, Zr, Mn, Sc, Fe,Ni, Co, W, Pt, and noble earths with the atomic numbers from 57 to 71,or alloys, or compounds containing one or more of these elements.
 2. Theimplant according to claim 1, wherein the particles consist of one ormore of the elements Y, Zr, Mn, Sc, Fe, Ni, Co, W, Pt, and noble earthswith the atomic numbers 57 to 71, or alloys, or compounds consisting ofone or more of these elements.
 3. The implant according to claim 1,wherein the particles have a mean diameter of 1 nm to 10 μm.
 4. Theimplant according to claim 1, wherein the particles are incorporatedinto a surface or into a near-surface region of the base body.
 5. Theimplant according to claim 1, wherein a number of the particles on thesurface of the base body ranges between 1×10³ and 1×10⁶ per mm².
 6. Theimplant according to claim 1, wherein a number of the particles in thevolume of the base body ranges between 1×10³ and 1×10⁹ per mm³.
 7. Theimplant according to claim 5, wherein a ratio of the mean particlediameter to the mean distance of the particles from each other rangesbetween 1:2 and 1:10.
 8. The implant according to claim 1, wherein amean distance between the particles ranges being between 200 nm and 100μm.
 9. An implant according to claim 1, wherein the implant is a stent.10. An implant according to claim 1 wherein the particles are Fe.
 11. Animplant according to claim 1 wherein the mean distance d_mean betweenparticles is optimized according to the relationship:$d_{mean} = {2 \cdot \sqrt{\frac{A_{protect}}{N \cdot \pi}}}$ whereprotected total area A_protect is obtained by assuming non-overlappingprotected regions from the sum over the distribution of the areasA_cathodic center protected by the individual particles:$A_{protect} = {\sum\limits_{i = {1\mspace{11mu} \ldots \mspace{14mu} N}}A_{i}^{{cathodic}\mspace{14mu} {center}}}$where N is the number of particles.
 12. A method for producing animplant having a base body comprising a biocorrodible magnesium alloy,wherein the method comprises the following steps: (i) providing a blankmade of the biocorrodible magnesium alloy; (ii) applying a non-aqueoussuspension of particles to the blank, the particles comprising one ormore of the elements Y, Zr, Mn, Sc, Fe, Ni, Co, W, Pt, and noble earthswith the atomic numbers from 57 to 71, or alloys, or compoundscontaining one or more of these elements; and (iii) rolling theparticles into the surface or into the near-surface region of the blankto thereby result in the magnesium alloy containing a plurality ofstatistically distributed particles, wherein the mean distance of theparticles from each other is smaller than the hundredfold mean particlediameter, and the particles are incorporated into a surface or into anear-surface region of the base body.
 13. A method according to claim12, wherein the particles consist of one or more of the elements Y, Zr,Mn, Sc, Fe, Ni, Co, W, Pt, and noble earths with the numbers 57 to 71,or alloys, or compounds consisting of one or more of these elements. 14.A method according to claim 12, and further including the step ofproviding the particles in a quantity to result in the number of theparticles in the volume of the base body to range between 1×10³ and1×10⁹ per mm³, and wherein the particles have a mean diameter of 1 nm to10 μm.
 15. A method according to claim 12, and further comprising thestep of providing the particles in a quantity and are distributed toresult in a mean distance between the particles being between 200 nm and100 μm.
 16. A method for producing an implant having a base bodycomprising a biocorrodible magnesium alloy, wherein the method comprisesthe following steps: (i) providing a blank made of the biocorrodiblemagnesium alloy; (ii) applying particles having the above-mentionedcomposition to the blank, the particles comprising one or more of theelements Y, Zr, Mn, Sc, Fe, Ni, Co, W, Pt, and noble earths with theatomic numbers from 57 to 71, or alloys, or compounds containing one ormore of these elements; and (iii) melting the magnesium alloy in thenear-surface region of the blank to result in the magnesium alloycontaining a plurality of statistically distributed particles, whereinthe mean distance of the particles from each other is smaller than thehundredfold mean particle diameter, and the particles are incorporatedinto a surface or into a near-surface region of the base body.
 17. Amethod according to claim 16, wherein the particles consist of one ormore of the elements Y, Zr, Mn, Sc, Fe, Ni, Co, W, Pt, and noble earthswith the numbers 57 to 71, or alloys, or compounds consisting one ormore of these elements.
 18. A method according to claim 16 wherein thestep of applying the particles comprises applying an adhesion enhancingpolymer to a surface of the bland, applying the particles in powder formto the surface, and shaking the surface to achieve a homogenousdistribution of the particles.
 19. A method according to claim 16, andfurther including the step of providing the particles in a quantity toresult in the number of the particles in the volume of the base body torange between 1×10³ and 1×10⁹ per mm³, and wherein the particles have amean diameter of 1 nm to 10 μm.
 20. A method according to claim 16, andfurther comprising the step of providing the particles in a quantity andare distributed to result in a mean distance between the particles beingbetween 200 nm and 100 μm.